Prognostic value of pretreatment serum fibrinogen in young patients with small cell lung cancer: A cross‐sectional study

Abstract Objective To explored the prognostic value of pretreatment serum fibrinogen level in young patients with small cell lung cancer (SCLC). Methods The concentrations of serum fibrinogen of 183 young (<50 years old) SCLC patients were measured. The association of baseline serum fibrinogen level and clinical outcome was analyzed by survival analysis. Results Hyperfibrinogenemia was significantly associated with American Veterans Administration Lung Study Group stage and surgery treatment. The survival analysis indicated that patients with hypefibrinogenemia had worse outcome than patients with normal fibrinogen. Pretreatment serum fibrinogen level was identified as a worse independent survival predictor in young SCLC. The hazard ratio was 1.420 (95% confidence interval: 1.035−1.947). Conclusions Pretreatment serum fibrinogen is independent associated with overall survival in patients with young SCLC.


| INTRODUCTION
Lung cancer is the leading cause of cancer-related death in the world. 1 Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers, and 60% of cases present with extensive-stage (ES) disease. 2 SCLC is prone to metastasis widespread. While immunotherapy has been added as a treatment option in recent years, the prognosis of SCLC remains poor. 3 Accurate prognosis prediction for SCLC is crucial for the personalized treatment and medical management. Several laboratory variables have been founded as prognostic indicators for SCLC, such as serum pro-gastrin-releasing peptide (ProGRP), neuron-specifific enolase, and so on.
Fibrinogen is a pivotal element of the coagulation system, which plays a major role in regulating blood clotting, inflammation, and neoplasia. 4 Increased activity was associated with cancer cell growth and progression. 5 Hyperfibrinogenemia is related to malignancies, such as colorectal, 6 gastric, 7 and non-small cell lung cancer (NSCLC). 8 However, the prognostic value of pretreatment serum fibrinogen in SCLC remains unknown.
SCLC in young patients has unique socioeconomic and clinical implications. 9 Very few studies have described SCLC in young (<50 years old) patients. 9,10 The study aims to explore the impact of baseline serum fibrinogen on clinical outcome in young patients with SCLC. We hypothesize that pretreatment serum fibrinogen concentration is related to overall survival (OS) of young patients with SCLC.

| Data collection
The electronic medical records of SCLCA patients were extracted and analyzed by the research team. Information evaluated included age at diagnosis, sex, smoking status, tumor histology, SCLC stage according to the Veteran's Administration Lung Group's 2-stage (VALG) classification, level of baseline serum fibrinogen, albumin, triglyceride, and blood sugar, as well as treatment protocol, and survival outcome.
Follow-up was performed at 6-month intervals until death, or until the last date of December 31, 2022. OS was defined as the time from the date of diagnosis until death due to any cause or the date the patient was last seen alive. Serum fibrinogen concentration of ≥4.0 g/L was defined as hyperfibrinogenemia, and concentration of 2.0−4.0 g/L was considered normal.

| Statistical analysis
Data for categorical variables were expressed as frequency rates and percentages and were compared using the χ 2 test. Continuous variables were described using mean, median, and interquartile range values, and differences between groups were compared using the Mann−Whitney U test.

| Patients characteristics
As shown in Table 1

| Correlation of serum fibrinogen level with clinical features
The median of pretreatment serum fibrinogen level was 3.85 g/L (range: 3.03-5.12 g/L) for all SCLC patients. Of 183 patients, 84 (45.9%) had hypefibrinogenemia (≥4 g/L), and 99 patients (54.1%) had normal serum fibrinogen concentration (2−4 g/L). Pretreatment serum fibrinogen level was correlated with albumin level and blood sugar level. Patients with hyperfibrinogenemia had significantly lower albumin levels (39.63 vs. 42.27 g/L, p < 0.001) and higher blood sugar levels (5.66 vs. 5.11 mmol/L, p = 0.009) than in patients with normal fibrinogen. Moreover, pretreatment serum fibrinogen level was significantly correlated with VALG stage and surgery treatment.
Fibrinogen concentration was markedly higher in ES than in LS (4.24 vs. 3.18 g/L, p < 0.001), and in patients without surgery than in those with surgery (3.94 vs. 3.16 g/L, p = 0.023) ( Table 1).

| Relationship between hyperfibrinogenemia and the frequency of venous thromboembolism
Among 183 young SCLC patients, 12 patients had venous thrombosis, with an incidence rate of 6.6%. Hyperfibrinogenemia was associated with venous thrombosis in young SCLC patients. Patients with hyperfibrinogenemia had a higher incidence of venous thromboembolism when compared to patients with normal fibrinogen level (8 cases, 66.7% vs. 4 cases, 33.3%, p = 0.014).

Key points
• Serum fibrinogen level was inversely correlated with overall survival of young small cell lung cancer (SCLC).
• Serum fibrinogen concentration was significantly associated with American Veterans Administration Lung Study Group stage.
• Pretreatment serum fibrinogen was an independent prognostic factor in young SCLC.

| Changes in fibrinogen of SCLC patients after treatment
As shown in Figure 1, follow-up fibrinogen level after the fourth treatment cycle was tested. The fibrinogen level was significantly decreased after chemotherapy and radiation therapy (p < 0.001 for both).
There was no significantly change in fibrinogen level after surgery (p = 0.731).

| Univariate and multivariate analysis of OS in SCLC
The results of univariate and multivariate cox regression analysis of OS in young SCLC patients were shown in Table 2. VALG stage, surgery treatment, and pretreatment fibrinogen level were significantly associated with OS in young SCLC by univariate analysis (p < 0.005 for all).
LS, surgery, and low pretreatment fibrinogen level were associated with a prolonged OS. Gender, smoking history, chemotherapy, and radiotherapy were not associated with OS on regression analysis.  (Figure 2).

| DISCUSSION
This was a retrospective study on the association between the coagulation and outcome in young patients with SCLC. As we know, this is the first study to investigate prognostic value of serum fibrinogen in young patients with SCLC. We demonstrated that pretreatment serum fibrinogen level was an independent prognostic biomarker for OS in young SCLC.
The correlation of the progression of human cancers and coagulation function has been studied for decades. The activation of fibrinolysis is generally associated with invasion, metastasis, and death. The risk of venous thrombosis is higher in NSCLC than those in cancer-free patients. 11 Hypercoagulability generally means more aggressive in cancer patients. Higher concentration of D-dimer, 12 antithrombin III content, 13 and platelet count 14 are associated with worse outcome in NSCLC. Moreover, high serum fibrinogen concentration is related to worse outcome in NSCLC. 15 In this study, we found that hyperfibrinogenemia was associated with venous thrombosis in young SCLC patients.
Patients with hyperfibrinogenemia had a higher risk of venous thromboembolism than those patients with normal fibrinogen level. Higher concentration of fibrinogen was associated with worse outcome in young SCLC.
Our study demonstrated that pretreatment serum fibrinogen level was correlated with albumin level and blood sugar level.
Patients with hyperfibrinogenemia had significantly lower albumin levels and higher blood sugar levels than in patients F I G U R E 1 Changes in fibrinogen of SCLC patients after treatments. The fibrinogen level was significantly decreased after chemotherapy and radiation therapy (p < 0.001 for both). There was no significantly change in fibrinogen level after surgery (p = 0.731). SCLC, small cell lung cancer.

CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
Data of this study are available from the corresponding authors upon reasonable request.

TRANSPARENCY STATEMENT
The lead author Dan Liu affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.